Substituted 3, 4-dihydro-3-phenyl-4-hydroxy-4-{[(amino)alkoxy (or alkylthio)]phenyl}isothiochroman



United States Patent SUBSTITUTED 3,4 DIHYDRO 3 PHENYL-4-HY- DROXY-4-{[(AMINO)ALKOXY (OR ALKYLTHIOH PHENYLHISOTHIOCHROMAN Ronnie R. Crenshaw, De Witt, N.Y., assignor to Bristol- Myers Company, New York, N.Y., a corporation of Delaware No Drawing. Filed Aug. 24, 1964, Ser. No. 391,789

13 Claims. (Cl. 260293.4)

This invention relates to novel compounds. More particularly, this invention relates to novel compounds which possess valuable utility as oral antifertility agents, and relates to intermediates useful in the preparation thereof. In another aspect, this invention relates to a novel method of inhibiting pregnancy.

It is an object of this invention to provide a new class of chemical compounds. It is another object of the present invention to provide novel compounds having antifertility activity. It is a further object of the present invention to provide a novel method of inhibiting pregnancy.

These and other objects which may appear as the specification proceeds are achieved by this invention which comprises the provision of compounds selected from the group consisting of compounds having the following formula and the pharmaceutically acceptable nontoxic salts thereof. In Formula I,

n is a whole integer from 1 to 6 inclusive;

R R R and R each represent a member selected from the group consisting of hydrogen, chloro, bromo, iodo, fluoro, trifiuoromethyl, (lower)alkyl, (lower) al-koxy, di(lower)alkylamino, di(lower)alkylsulfamyl, (lower) alkanoyl, phenyl, phenoxy, benzyl and cycloalkyl radicals having from 5 to 7 carbon atoms inclusive, e.g. cyclopentyl, cyclohexyl and cycloheptyl;

R and R each represent a member selected from the group consisting of (lower)alkyl, (lower)a1kenyl, (lower) alkyny1, phenyl, phenyl(lower)alkyl, cycloalkyl radicals having from 3 to 7 carbon atoms inclusive, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclo heptyl, and when taken together with -N constitute a heterocyclic ring selected from the group consisting of pyrrolidino, (lower)alkylpyrrolidino, di(lower)alkylpy-rrolidino, piperidino, (lower)alkylpiperidino, di(lower) alkylpiperidino, morpholino, (lower)alkylmorpholino, di- (lower)alky1morpholino,.tetrahydropyridino, e.g. 1,2,5,6- tetrahydropyridino, (lower)alkyltetrahydropyridino, di- (lower) alkyltetrahydropyridino, N (lower)alkylpiperazino, N'-(lower) a1kyl(lower)alkylpiperazino, N-(lower)alkyl di(lower)alkylpiperazino, hexarnethyleneimino, (lower) a1kylhexamethyleneimino, di (lower) alkylhexamethyleneimino;

X is a member selected from the group consisting of oxygen and sulfur.

The pharmaceutically acceptable nontoxic salts include the organic and inorganic acid addition salts, e.g., those prepared from acids such as hydrochloric, sulfuric, sulfamic, tartaric, fumaric, hydrobromic, hydriodic, glycolic, citric, maleic, phosphoric, succinic, acetic, nitric and the like.

The term (lower)alkyl as used herein means both straight and branched chain alkyl radicals containing from 1 to 8 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, iso'butyl, t-butyl, amyl, hexyl, 2-et-hylhexyl, etc.

The term (lower)alkenyl as used herein means both straight and branched chain alkenyl radicals containing from 2 to 8 carbon atoms, e.g. ethenyl, allyl, l-propenyl, l-butenyl, 3-butenyl, 2-methyl-1-propenyl, 3-pentenyl, 1- hexenyl, 7-octenyl, etc.

The term (lower)alkynyl as used herein means both straight and branched chain alkynyl radicals containing from 2 to 8 carbon atoms, e.g. ethinyl, propargyl, 1- butinyl, 2-butinyl, 1,1-dimethylpropargyl, l-pentinyl, 1- heptinyl, etc.

Similarly, where the term (lower) is used as part of the description of another group, e.g., (lower)alkoxy, it refers to the alkyl portion of such group which is therefore as described in connection with (lower)alkyl.

Preferred compounds of the present invention are those having the following formulae wherein n, R R R R R and R are as represented above.

Still more preferred compounds of the present invention are those having the following formulae herein n, R R R and R are as represented above. The compounds of this invention are valuable pharma- :utical agents. They possess antifertility activity and e orally active antifertility agents in mammals.

The antifertility tests of the compounds of the present .vention were carried out on mice. The compounds were lministered oral-1y to adult female mice for six days. single dose was administered three days before mating id single doses were administered daily for five days iring mating. The mice were sacrificed on the eleventh ry following mating and their uteri examined for imantation sites. The absence of implantation sites in the eri indicated that pregnancy was completely inhibited. 'hen, for example, the preferred compound of the prestt invention, 3,4-dihydro-7-methoxy-3-phenyl-4-hydroxy- {p-[2-(l-pyrrolidyl)ethoxy]phenyl}-1H-2 benzothio- 'ran hydrochloride, was administered orally at doses as w as 0.1 mgm./kg./ day, no implantation sites were obrved in any of the mice tested; hence pregnancy was tmpletely inhibited in each of the mice.

The compounds of the present invention are prepared I the following series of reactions.

A. A benzyl halide of the formula CH Hal herein R and R are as described above, and Hal is loro, brorno or iodo, is reacted with thiourea in the esence of an inert solvent, such as ethanol, at reflux rnperature, and then the mixture is heated at reflux temrature in the presence of a base, such as sodium hyoxide, to produce a toluenethiol of the formula rking the compounds of Formula X is described in chters Organic Chemistry, vol. III, 3rd Edition, at p.

B The toluenethiol prepared in Step A is reacted with u-halophenylacetic acid of the formula I) (II) R HOG-(EH- 2S Hal R4 terein Hal, R and R are as described above, in the :sence of a base such as sodium hydroxide and an inert solvent such as ethanol at reflux temperature to produce a benzylthiophenylacetic acid of the formula (XII) (H) HOC\ R4 R2 CH1 wherein R R R and R are as described above.

C. The benzylthiophenylacetic acid prepared in Step B is cyclized by first reacting the compound with thionyl chloride in the presence of benzene at reflux temperature to convert the benzylthiophenylacetic acid to a benzylthiophenylacetyl chloride and then reacting the chloride with a dehydrating agent (Lewis acid), such as stannic chloride at a temperature of about 0 C. to produce a 3-phenyl-4-isothiochromanone of the formula (XIII) I? /C\ R I CH g R /S R4 on,

wherein R R R and R are as described above.

D. The compounds of the present invention are prepared by the reaction of the 3-phenyl-4-isothiochromanone prepared in Step C with a Grignard reagent of the formula 1 (XIV) R Ra wherein Hal, n, X, R and R are as described above. The reaction is preferably carried out in the presence of an inert solvent, e.g. tetrahydrofuran, and at the boiling point of the reaction mixture.

Alternatively, the compounds of the present invention may be prepared by the reaction of the 3-phenyl-4-isothiochromanone with an organo-lithium compound of the formula (X V) R wherein n, X, R and R are as represented above.

The starting materials used in the processes described herein are compounds which are either commercially available, well-known in the art, or easily prepared in accordance with standard organic procedures previously described in the chemical literature.

For example, the benzyl halides used in Step A are prepared by the halogenation of a benzyl alcohol of the formula (XVI) CHaOH wherein R and R are as described above, with a hydrogen halide gas, e.g., hydrogen chloride, in the presence of an inert solvent such as ethyl ether. An alternate method of preparing the benzyl halides consists of reacting a benzyl alcohol with thionyl chloride in the presence of pyridine. Methods for the preparation of benzyl halides are described by L. A. Brooks and H. R. Snyder, Org. Syn., coll. vol. 3, p. 698; Tsukamoto et al., Pharm. Bull. (Japan), vol. 3, p. 239 (1955); Textbook of Organic Chemistry, Fieser and Fieser, 1950, pp. 430, 517-518; and Richters Organic Chemistry, A. I. Mee, 3rd Edition, vol. III, p. 253.

The Grignard reagents having the Formula XIV used in Step D are prepared by procedures well-known in the art. The reagents are prepared by the reaction of mag nesium with a halo-benzene of the formula 5 (XVII) /R X-o..Hi..-N

Hal R wherein Hal, X, n, R and R are as described above, in the presence of an inert solvent, e.g., tetrahydrofuran. The halobenzenes of Formula XVII used in the preparation of the Grignard reagents are prepared by well-known procedures, e.g. cf. A. Burger, E. L. Wilson, C. O. Brindley and F. Bernheim, J. Am. Chem. Soc., vol. 67, pp. 1416-1419 (1945); and South African Patent No. 62/ 3,277, which describe the reaction of a halo-phenol or a halo-thiophenol with a tertiary aminoalkyl halide of the formula (XVIII) u wherein R and R are as described above, and a halo alkanol of the formula wherein Hal and n are as described above, as described by R. B. Moffett, J. Org. Chem., vol. 14, p. 862 (1949). The tertiary aminoalkanols can also be prepared by heating a secondary amine of Formula XIX with a halo alkanoic acid ester and then reducing the aminoalkanoic acid ester thus formed with a reducing agent such as lithium aluminum hydride, as described by Mofiett. The preparation of each of the foregoing intermediates used in the preparation of the Grignard reagents is well-known in the art.

The compounds of this invention may be administered as the free bases or in the form of their nontoxic addition salts. They may be compounded and formulated into pharmaceutical preparations in unit dosage form for oral administration with organic or inorganic solid materials or liquids which are pharmaceutically acceptable carriers. The compositions may take the form of tablets, powder granules, capsules, suspensions, solutions and the like. Such compositions are considered within the scope of this invention.

The compositions of this invention when administered orally, in an effective amount, are effective in the inhibition of pregnancy. The usual daily dosage is from about 0.1 to 200 mgm./kg.

The following examples are intended to illustrate the invention described herein without unduly restricting it.

EXAMPLE 1 Preparation of m-methoxy-a-toluenethiol C1130 CH,sH

A solution of m -methoxybenzyl chloride (79.5 gm.), thiourea (38.6 gm), and ethanol (250 ml.) was refluxed on a steam cone for four hours. Sodium hydroxide (30.4 gm.) in water (300 ml.) was then added and the mixture refluxed under a nitrogen atmosphere for 2.5 hours.

The mixture was cooled and the lower layer of crude mercaptan separated. The aqueous phase was acidified with dilute sulfuric acid and then extracted with ether. The ether extracts were added to the crude mercaptan layer and the whole was washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed and the residual oil (67 gm.) distilled at 118- C./0.650.70 mm. to yield 59.2 gm. (76%) of m-methoxy-a-toluenethiol as a colorless liquid. The major portion distilled at 119" C./0.65 mm.; n =1.5720; iodine equivalent, 152 (calcd. for C H OS, 154).

EXAMPLE 2 Preparation of (m-mthoxybenzyllhio)phenylacetic acid t -Q omo s Cfig A solution of m-methoxy-a-toluenethiol (39.2 gm.) and aebromophenylacetic acid (54.8 gm.) in ethanol (185 ml.) and aqueous sodium hydroxide (1 N, 508 ml.) was stirred at 22 C. for 17 hours.

About one-third of the solvent was removed at 15 mm., and the residue was extracted with two portions of ether which were discarded. The aqueous phase was then acidified with dilute hydrochloric acid and extracted several times with ether. The combined ether extracts were washed with water, dried and evaporated to give the prod uct, (m-methoxybenzylthio)phenylacetic acid, as a deep yellow syrup; yield 68.8 gm. (94%).

The material was characterized as the hydrated sodium salt, M.P. 93-95 C. (dioxane-ether).

Analysis.Calcd. for C H NaO S-I-I O: C, 58.58; H 5.22. Found: C, 58.70; H, 4.76.

EXAMPLE 3 Preparation of 7-methoxy-3-phenyl-4- isothiochromanone or i.

A mixture of the crude (m-methoxybenzylthio)phenyl acetic acid (31.7 gm.), thionyl chloride (39.2 gm.) ant benzene (75 ml.) was stirred at reflux for 25 minutes The solution was concentrated at reduced pressure (2: mm), fresh benzene added and the solution again con centrated; the operation was repeated to ensure com plete removal of the thionyl chloride.

The crude acid chloride thus obtained was dissolve in benzene (100 ml.) and the solution stirred at 0-5 C. while a solution of stannic chloride (18.8 ml.) i1 benzene (48 ml.) was added over a 15-minute period The mixture was stirred at 0 C. for an additional 1 minutes, then poured onto a mixture of concentrate hydrochloric acid ml.) and ice.

Trituration gave brown solid which was extracted int ether. The ether was washed in succession with watei aqueous sodium bicarbonate, water and saturated brin solution. After drying, the ether solution was stirred wit decolorizing carbon for 1.5 hours. Filtration and evapore tion of the ether gave a syrup which was triturated unde Skellysolve B to give brown crystalline solid, yiel 22.5 gm. (76%), M.P. 7073 C.

Further recrystallizations from acetone-Skellysolv B gave the ketone of constant M.P. 8586 C.

Analysis.Calcd. for C H O S: C, 71.08; H, 5.22; 11.86; MW, 270. Found: C, 71.05; H, 5.21; S, 11.76; lW, 291 (ethanol, Mechrolab osmometer).

EXAMPLE 4 Preparation of I [2- p-brom pk enoxy ethyl] pyrrolidine N-(2-chloroethyl)pyrrolidine hydrochloride (31.6 gm.) as added to a solution of sodium methoxide (9.2 gm.) l absolute ethanol (75 ml.). After stirring for 15 mintes at 25 C., sodium chloride was separated by filtraon. The filtrate was added slowly over a period of 30 inutes to a hot solution of p-bromophenol (40.9 gm.) absolute ethanol (225 ml.) containing sodium meth- (ide (12.7 gm.).

After heating under reflux for three hours, the mix- .re was cooled, the precipitated salt was separated, and re solvent was removed under reduced pressure. The :sidual oil was dissolved in ether which was washed in lccession with 10% aqueous sodium hydroxide solu- Jn, water and saturated brine solution. Removal of e ether and distillation of the residue gave 26.0 gm. 5 1-[2-(p-bromophenoxy)ethyl]pyrrolidine, B.P. 138- l0 C./ 1.2 mm.

Analysis.-Calcd. for C H BrNOz NE, 270. Found, '1.

EXAMPLE 5 Preparation of 1- [2- (p-bromophenylthia ethyl] pyrrolidine N-(2-chloroethyl)pyrrolidine hydrochloride (23.8 gm.) is added to a solution of sodium methoxide (6.9 gm.) absolute ethanol (55 ml.). After stirring for 15 mines at 25 C., the sodiumchloride was separated, and e resultant clear solution was added dropwise over a riod of one hour to a solution under reflux of p-bromoiophenol (33.6 gm.) in absolute ethanol (170 ml.) ntaining sodium methoxide (9.6 gm).

After heating under reflux for three hours, the mixre was cooled, the precipitated salt was separated and e solvent was removed under reduced pressure. The sidual oil was dissolved in ether, and the solution was tracted in succession with aqueous sodium hyoxide solution, Water and saturated brine solution. Fter removal of the solvent, distillation gave 22.3 gm. 1-[2 (p bromophenylthio)ethyl]-pyrrolidine, B.P. 8 C./ 1.1 mm.

Analysis.Calcd. for C I-I BrNS: C, 50.35; H, 5.64; 27.92; N, 4.89. Found: C, 50.80; H, 5.62; Br, 28.40;

EXAMPLE 6 eparation of 3,4 dihydro' 7 methoxy-3-pheriyl-4-hydroxy 4 {p [2-(1-pyrrolidyl) eth0xy]phenyl}-1H-2- benzo thiopyran hydrochloride A solution of 7-methoxy-3-phenyl-4-isothiochromanone (6.70 gm.) in 74 ml. of dry tetrahydrofuran then was added rapidly and the resultant solution heated at reflux .for 16 hours.

The mixture was cooled, ether added, and then water (2.5 ml.) introduced dropwise while cooling in an ice bath. The precipitated magnesium salts were separated by filtration. The filtrate was diluted with additional ether and then washed several times with water, dried and evaporated.

The residual oil was taken up in ether which then was extracted with three 25-ml. portions of 0.5 N hydrochloric acid. The combined acid extracts were extracted with methylene chloride. Drying (sodium sulfate) and evaporation of the methylene chloride gave the alcohol as an oil; yield 4.5 gm. Trituration under acetone yielded 1.50 gm. crystalline solid, M.P. 158-162 C. Recrystallization from methylene chloride-ethyl acetate gave 0.9 gm, M.P. 176-177 C. with decomposition.

Analysis.Calcd. for C H C1NO S: C, 67.52; H, 6.50; N, 2.81. Found: C, 66.95; H, 6.49; N, 2.76, 2.91.

EXAMPLE 7 When, in the procedure of Example 1, m-methoxybenzyl chloride is replaced by an equal molar amount of benzyl chloride,

Z-methoxybenzyl chloride, 4-methoxybenzyl chloride, 2,4-dimethoxybenzyl chloride, 3,5-dimethoxybenzyl chloride, 2,3-dimethoxybenzyl chloride, 3,4-dimethoxybenzyl chloride, 3-ethoxybenzyl chloride, 3-propoxybenzyl chloride, 3-chlorobenzyl chloride, 3-rnethylbenzyl chloride, 4-ethylbenzyl chloride, 2,4-dimethylbenzyl chloride 2-propy1benzyl chloride, 3-trifiuoromethylbenzyl chloride, 4-iodobenzyl chloride, 2-bromobenzyl chloride, 3-fluorobenzyl chloride, 3,4-dichlorobenzyl chloride, 3-phenylbenzyl chloride, 4-benzylbenzyl chloride, 2-phenoxybenzyl chloride, 3-dimethylaminobenzyl chloride, 4-dimethylsulfamylbenzyl chloride, 3-acetylbenzyl chloride, 3-methoxy-4-methylbenzyl chloride, 3-cyclohexylbenzyl chloride, 2-cyclopentylbenzyl chloride, 4-cycloheptylbenzyl chloride and 3-methoxy-4-trifluoromethylbenzyl chloride,

respectively, there are obtained,

a-toluenethiol, 2-methoxy-a-toluenethiol, 4-m6thOXY-oc-t0lll6l16th10l, 2,4-dimethoxy-a-toluenethiol, 3,5 -dimethoxy-a-toluenethiol, 2,3-dimethoxy-rx-toluenethiol, 3,4-dimethoxya-toluenethiol, 3 -ethoxy-a-toluenethiol, 3-propoxy-u-toluenethiol, 3-chloro-a-tol-uenethiol, 3-methyl-a-toluenethiol, 4-ethyl-u-toluenethiol, 2,4-dimethyl-ot-toluenethiol, 2-propyl-ot-toluenethiol, 3-trifluoromethyl-m-toluenethiol, 4-iOdO-ot-t01ll6l16th10l, 2-bromo-a-toluenethiol,

3 -fluoro-a-toluenethiol,

9 3,4-dich1oro-a-toluenethiol, 3-phenyl-u-toluenethiol, 4-benzyl-u-toluenethiol, 2-phenoxy-a-toluenethi0l, S-dimethylamino-a-toluenethiol, 4-dimethylsulfamyl-a-toluenethiol, 3-acetyl-u-toluenethiol, 3-methoxy-4-methyl-a-toluenethiol, 3-cyclohexyl-u-toluenethiol, 2-cyclopentyl-a-toluenethiol, 4-cycl0heptyl-a-toluenethiol and 3-methoxy-4-trifluoromethyl-a-toluenethiol,

respectively.

EXAMPLE 8 When, in the procedure of Example 2, m-methoxyutoluenethiol is replaced by an equal molar amount of each of the products of Example 7, there are obtained,

benzylthiophenylacetic acid, (Z-methoxybenzylthio phenylacetic acid, (4-methoxybenzylthio phenylacetic acid, (2,4-dimethoxybenzy1thio phenyl acetic acid, (3 ,5 -dimethoxybenzylthio phenylacetic acid, (2,3-dirnethoxybenzylthio phenylacetic acid, (3 ,4-dimethoxybenzylthio phenylacetic acid, (3-ethoxybenzylthio phenylacetic acid, (3-pr0poxybenzylthio phenylacetic acid, (3 -chlorobenzylthio phenylacetic acid, (3 -m ethylb enzylthio phenylacetic acid, (4-ethylbenzylthio phenylacetic acid, (2,4-dimethylbenzylthio phenylacetic acid, (2-propylbenzylthio phenylacetic acid, (3-trifluor0methylbenzylthio) phenylacetic acid, (4-iodo'benzy1t-hi0 phenylacetic acid, 2-bromobenzylthio phenylacetic acid, (3-fluorobenzylthio phenylacetic acid, (3 ,4-dichlorbenzylthio phenylacetic acid, (3 -phenylb enzylthio phenylacetic acid, (4-benzylb enzylthio phenyl acetic acid, (2-phenoxybenzylthio phenylacetic acid, (3-dimethylaminobenzylthio phenylacetic acid, (4-dimethylsulfamylbenzylthio phenylacetic acid, (3 -acetylbenzylthio phenylacetic acid, (3-methoxy-4-rnethylbenzylthi0 phenylacetic acid, (3 -cyclohexylb enzylthio phenylacetic acid, (2- cyclopentylbenzylthio phenylacetic acid, (4-cycloheptylbenzylthio phenylacetic acid and (3-rnethoxy-4-trifluoromethylb enzylthio phenylacetic acid,

respectively.

EXAMPLE 9 When, in the procedure of Example 2, oc-bfOITlOPhGIlYl acetic acid is replaced by an equal molar amount of a-brorno-4-methylphenylacetic acid, a-bromo-4-trifluoromethylphenylacetic acid, m-bromo-Z-chlorophenylacetic acid, a-bromo-3-bromopheny1acetic acid, a-bromo-4-iodophenylacetic acid, a-bromo-3-fluorophenylacetic acid, a-bromo-Z-ethylphenylacetic acid, a-bromo-2,4-dichlorophenylacetic acid, a-bromo-4-methoxyphenylacetic acid, a-bromo-3-ethoxyphenylacetic acid, a-bromo-2-propylphenylacetic acid, a-bromo-4-phenylpheny1acetic acid, u-brorno-3-phenoxyphenylacetic acid, a-bromo-2rpropoxyphenylacetic acid, a-bromo-2-methy1-4-trifluoromethylphenylacetic acid, a-bromo-4-benzylpheny1acetic acid, a-br0mo-3-cycl0hexy1phenylacetic acid, a-bromo-2-cycl0pentylphenylacetic acid, a-bromo-4-acetylphenylacetic acid, a-bromo-3-dimethylsulfamylphenylacetic acid,

a-bromo-4-dimethylamiuophenylacetic acid, a-bromo-3-diethylamin0pheny1acetic acid, a-bromo-4-fiuorophenylacetic acid, a-brom0-4-chloropheny1acetic acid, a-bromo-2-diethylaminophenylacetic acid, a-bromo-3-cycloheptylphenylacetic acid, wbromo-4-bromophenylacetic acid and a-bromo-3-propanoylphenylacetic acid,

respectively there are obtained,

-m-methoxybenzylthio-4-methylphenylacetic acid,

m-methoxybenzylthio-4-trifluoromethylphenylacetic acid, m-methoxybenzylthio-2-chlor0phenylacetic acid, m-methoxybenzylthio-3-br0mophenylacetic acid, m-methoxybenzylthio-4-i0dophenylacetic acid, m-methoXybenzylthio-3-fiu0rophenylacetic acid, m-methoxybenzylthiO-Z-ethylphenylacetic acid, m-rnethoxybenzylthio-2,4-dichlorophenylacetic acid, m-methoxybenzylthio-4-methoxyphenylacetic acid, m-methoxybenzylthio-3-ethoxyphenylacetic acid, m-methoxybenzylthio-2-propylphenylacetic acid, rn-methoxybenzylthio-4-phenylpheny1acetic acid, m-methoxybenzylthio-3-phenoxyphenylacetic acid, m-methoxybenzylthio-2-propoxyphenylacetic acid, rn-methoxybenzylthio-2-methyl-4-trifiuoromethylphenylacetic acid, m-methoxybenzylthio-4-benzylphenylacetic acid, m-methoxybenzylthio-3-cyclohexylphenylacetic acid, m-rnethoxybenzylthio-2-cyclopentylphenylacetic acid, m-methoxybenzylthio-4-acetylphenylacetic acid, m-methoxybenzylthio-3-dimethylsulfamylphenylacetic acid, m-rnethoxybenzylthio-4-dimethylaminophenylacetic acid, m-methoxybenzylthi0-3-diethy1aminophenylacetic acid, m-methoxybenzylthio-4-fluorophenylacetic acid, In-methoxybenzylthio-4-chlorophenylacetic acid, m-methoxybenzylthio-2-diethylaminophenylacetic acid, m-methoxybenzylthio-3-cycloheptylphenylacetic acid, m-methoxybenzylthio-4-bromophenylacetic acid and rn-rnethoxybenzylthio-3-propan0ylphenylacetic acid,

respectively.

EXAMPLE 10 When, in the procedure of Example 3, (m-methoxybenzylthio)pheny1acetic acid is replaced by an equal molar amount of each of the products of Example 8, there are obtained,

3-phenyl-4-isotl1iochromanone, 8-methoxy-3-phenyl-4-isothiochromanone, 6-methoxy-3 -phenyl-4-isothiochromanone, 6,8-dimethoxy-3-phenyl-4-isothiochrornanone, 5,7-dimethoxy-3-phenyl-4-isothiochrornanone, 7,8-dimethoxy-3-pheny1-4-is0thiochromanone, 6,7-dimethoxy-3-phenyl-4-isothiochromanone, 7-eth0xy-3-phenyl-4-isothioch-romanone, 7-propoxy-3 -phenyl-4-isothiochromanone, 7-chloro-3-phenyl-4-isothiochromanone, 7-methyl-3-phenyl-4-isothiochnomanone, 7-ethyl-3 -phenyl-4-isothi0chromanone, 6,8-dimethyl-3 -phenyl-4-isothiochromanone, 8-propyl-3-phenyl-4-isothiochrornanone, 7-trifiuoromethy1-3-phenyl-4-isothiochromanone, 6-iodo-3-phenyl-4-isothiochromanone,

8-bromo-3 -phenyl-4-isothiochromanone, 7-fiuoro-3 -phenyl-4-isothi0chrornanone, 6,7-dichlor0-3-phenyl-4-isothiochromanone, 7-phenyl-3-phenyl-4-isothiochromanone, 6-benzyl-3-phenyl-4-isothiochromanone, 8-phenoxy-3-phenyl-4-isothiochromanone, 7-dimethylamino-3 -phenyl-4-isothiochromanone, 6-dimethylsulfamyl-3-phenyl-4-is0thiochr0manone, 7-acetyl-3-phenyl-4-isothiochromanone, 6-methy1-7-methoxy-3-phenyl-4-isothiochromanone, 7-cycIohexyl-3 -phenyl-4-isothiochromanone, 8-cyclopentyl-3-phenyl-4-isothiochrornanone,

3,4-dihydro-7-methoxy-3 -phenyl-4-hydroxy-4-{o- [2- (N,N- v

diethylamino) ethylthio]phenyl}-1H-2-benzothiopyran, 3 ,4-dihydro-7-methoxy-3 -phenyl-4-hydroxy-4-{m- 2- (N, N-diethylamino ethylthio 1 phenyl}- I-H-Z-benzothio- Py 3,4-dihydro-7-methoxy-3aphenyl-4-hydroxy-4-{o- [2-( 1- pyrrolidyl)ethoxy]phenyl}-1H-2-benzothiopyran, 3,4-dihydro-7-methoxy-3-phenyl-4-hydroxy-4-{m- [2- 1- pyrrolidyl) ethoxy]-phenyl}-1H-Z-benzothiopyran, 3,4-dihydro-7-methoxy-3-phenyl-4-hydroxy-4-{o-[2-(1- pyrrolidyl) ethylthio] phenyl}- lH-2-benzothiopyran and 3,4-dihydro-7-methoxy-3-phenyl-4-hydroxy-4-{rn- 2-( 1- pyrrolidyl)ethylthio] phenyl}-1H-2-benzothiopyran,

respectively.

EXAMPLE 15 Preparation of 3,4-dihydro-7-methoxy-3-phenyl 4 hydr0xy-4-{p-[Z-(diethylamino)ethoxy]phenyl} 1H 2- benzothiopyran hydrochloride CHzCHs o-orrzorn-N Using the procedure described above in Example 6, a Grignard reagent was prepared from -p-(2-diethylam1noethoxy)bromobenzene (10.10 gm.) and magnesium turnings (0.90 gm.) in tetrahydrofuran (105 1111.). v

A solution of 7-methoxy-3-phenyl-4-isothiochromanone (10.00 grn.) in tetrahydrofuran (110 ml.) then was added rapidly to the hot Grignard solution and the resultant solution was heated at reflux for 16 hours.

.The mixture was cooled, ether was added, and then water (3.7 ml.) was introduced slowly while cooling in an ice bath. The precipitated magnesium salts were separated by filtration. The filtrate was diluted with additional ether and the resultant solution was washed several times with water, dried and concentrated.

The residual oil was taken up in ether and the solution was extracted with three 39-ml. portions of 0.5 N hydrochloric acid. The combined acid extracts were extracted with methylene chloride. Drying (sodium sulfate) and evaporation of the methylene chloride gave 3,4-dihydno- 7-methoxy-3-phenyl-4-hydroxy-4-{p [2 (diethylamino) ethoxy]phenyl}-lH-2benzothiopyran as an oil. Trituration under a mixture of methylene chloride and ethyl acetate gave 1.95 gm. (11%) crystalline solid, 3,4-dihydro-7- methoxy-3-phenyl-4-hydroxy-4 {p [2 (diethylamino) ethoxy]phenyl}-1H-2 benz0thi0pyran hydrochloride, M.P. 169-170" C. with decomposition. The material was purified "for analysis by recrystallization to a constant melting point of 186.5-187.5 C. with decomposition.

Analyis.--Calcd. for C H ClNO S: C, 67.25; H, 6.85; Cl, 7.09; N, 2.79; S, 6.41. Found: C, 67.30, 67.22; H, 6.96, 6.96; Cl, 6.86; N, 2.73; S, 6.45.

Thus, it is apparent from the foregoing description that CHzCHz 18 the objects of this invention have been attained. Novel compounds have been invented which have antifertility activity and inhibit pregnancy. In addition, a novel method of inhibiting pregnancy has been described.

While this invention has been described and exemplified in terms of its preferred embodiment, those skilled in the art will appreciate that modifications can be made without departing from the spirit and scope of this invention.

What is claimed is:

1. A compound selected from the group consistint of compounds of the formula Rs R1 Q R2 wherein n is a whole integer from 1 to 6 inclusive;

R R R and R each represent a member selected from the group consisting of hydrogen, chloro, bromo, iodo, fluoro, trifluoromethyl, (lower)alkyl, (lower) alkoxy, di (lower) alkylamino, di (lower) alkylsulfamyl, (lower)alkanoy1, phenyl, phenoxy, benzyl and cycloalkyl radicals having from 5 to 7 carbon atoms inclusive;

R and R each represent a member selected from the group consisting of (lower)alkyl, (lower) alkenyl, (lower)alkynyl, phenyl, phenyl(lower)alkyl, cyclo alkyl radicals having from 3 to 7 carbon atoms inclusive, and when taken together with -N constitute a heterocyclic ring selected from the group consisting of pyrrolidino, (lower)alkylpyrrolidino, di(lower) alkylpyrrolidino, piperidino, (lower) alkylpiperidino, di(lower)alkylpiperidino, morpholino, (lower) alkylmorpholino, di(lower) alkylmorpholino, tetrahydropyridino, (lower)alkyltetrahydropyridino, di (lower) alkyltetrahydropyridino, N'- (lower) alkylpiperazino, N'-(lower)alkyl-(lower)alkylpiperazino, N- (lower) alkyl-di (lower) alkylpiperazino, hexamethyleneimino, (lower)alkylhexamethyleneimino, di- (lower) alkylhexamethyleneirnino;

X is a member selected from the group consisting of oxygen and sulfur;

and the pharmaceutically acceptable nontoxic salts thereof.

2. A compound selected from the group consisting of compounds of the formula R5 0C H: N

wherein n is a whole integer from 1 to 6 inclusive;

R R R and R each represent a member selected from the group consisting of hydrogen, chloro, bromo, iodo, fluoro, trifiuoromethyl, (l-ower)alkyl, (lower) alkoxy, di(lower)alkylamino, di(lower)alkylsulfamyl, (lower) alkanoyl, phenyl, phenoxy, benzyl and cycloalkyl radicals having from 5 to 7 carbon atoms inclusive;

0,3 1 9 R and R each represent a member selected from the group consisting of (lower) alkyl, (lower)alkenyl, lower) alkynyl, phenyl, phenyl(lower)alkyl, cycloalkyl radicals having from 3 to 7 carbon atoms inclusive, and when taken together with N constitute a heterocyclic ring selected from the group consisting of pyrrolidino, (lower)alkylpyrrolidino, di(lower)alkylpyrrolidino, piperidino, (lower)alkylpiperidino, di(lower)alkylpiperidino, morpholino, (lower) alkylmorpholino, di (lower) alkylmorpholino, tetrahydropyridino, (lower) alkyltetrahydropyridino, di(lower) alkyltetrahydropyridino, N'- (lower) alkyl piperazino, N'-(lower) alkyl- (lower) alkylpiperazino, N (lower)alkyl di(lower)alkylpiperazino, hexamethyleneimino, (lower)alkylhexamethyleneimino, di( lower) alkylhexamethyleneimino;

,nd the pharmaceutically acceptable nontoxic salts there- 3. A compound selected from the group consisting of ompounds of the formula R2 herein n is a whole integer from 1 to 6 inclusive;

R R R and R each represent a member selected from the group consisting of hydrogen, chloro, bromo, iodo, fluoro, trifiuoromethyl, (lower)alkyl, (lower) alkoxy, di(lower) alkylamino, di(lower) alkylsulfamyl, (lower) alkanoyl, phenyl, phenoxy, benzyl and cycloalkyl radicals having from 5 to 7 carbon atoms inclusive;

R and R each represent a member selected from the group consisting of (lower) alkyl, (lower) alkenyl, (lower)alkynyl, phenyl, phenyl(lower) alkyl, cycloalkyl radicals having from 3 to 7 carbon atoms inclusive, and when taken together with N constitute a heterocyclic ring selected from the group consisting of pyrrolidino, (lower)alkylpyrrolidino, di(lower)alkylpyrrolidino, piperidino, (lower)alkylpiperidino, di(lower)alkylpiperidino, morpholino, (lower) alkylmorpholino, di lower) alkylmorpholino, tetrahydropyridino, (lower)alkyltetrahydropyridino, di (lower) alkyltetrahydropyridino, N'- (lower) alkylpiperazino, N'-(lower) alkyl-( lower) alkylpiperazino, N (lower)alkyl di(lower)alkylpiperazino, hexamethylene'imino, (lower)alkylhexamethyleneimino, di (lower) alkylhexamethyleneimino;

1d the pharmaceutically acceptable nontoxic salts there- 4. A compound having the formula H 0 6-0-0 nHit-N herein It is a whole integer from 1 to 6 inclusive. 5. A compound having the formula (lower) alkoxy (lower)a1kyl (lower) alkyl 20 wherein n is a whole integer from I to 6 inclusive. 6. A compound having the formula /(lower) alkyl 5 H0 & -oonH2-N (lower) alkyl 10 (lower) alk0xy wherein n is a whole integer from 1 to 6 inclusive. '7. The compound having the formula HO OCH2CH2-N/ CHaO- \/S 8. The pharmaceutically acceptable nontoxic salts of the compound of claim 7.

9. The compound having the formula HO O-CHzCHzN CHBO 10. The compound having the formula CH3 F HO Q-O-( JHCIh-N OHaO- 11. The compound having the formula HO @s-omom-N \v CH 0- S a 12. The compound having the formula HO -o-omom-n -CFa cH3o 13. The compound having the formula /CHzCHa HO @OCH2CH2N\ CH3CH3 CHaO S References Cited UNITED STATES PATENTS 3,164,607 1/1965 Lednicer 260-326.5

WALTER A. MODANCE, Primary Examiner.

7 A. D. SPEVACK, Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA
 9. THE COMPOUND HAVING THE FORMULA 